The long term objective of this proposal is to understand the mechanism by which human papillomaviruses contribute to the development of anogenital malignancies. Specific HPV types including HPV 16, 18, and 31 are the etiological agents of most cervical cancers. In these lesions the E6 and E7 genes are selectively retained and expressed. In tissue culture both E6 and E7 genes are-required for the high frequency immoralization of human keratinocytes, implicating them as oncoproteins. Insight into the mechanism of transformation comes from the observations that these viral proteins associate with the cellular regulators pS3 and Rb. This association leased to the abrogation of the normal function of these proteins which most likely involves transcriptional control. Rb binds several transcription factors resulting in the repression and activation of expression of selected cellular genes. The pS3 protein is a site specific DNA-binding protein which can activate the expression of associated genes. In addition, when expressed at high levels p53 interacts with basal transcription factors to repress expression from genes containing TATA but not initiator elements. In this proposal, we will examine the biochemical and functional activities of the B6 and E7 proteins centering on their association with cellular regulators. We will specifically examine: (1) Is degradation of pS3 by E6 necessary for immortalization or is binding sufficient? (2) How does E6 affect the transactivating, repressing and DNA-binding properties of p53? (3) Does E6 contribute to immoralization and alteration of differentiation through an indirect mechanism by abrogating the normal surveillance properties of p53 for DNA damage? (4) Is the binding of other cellular proteins important for the function of E6? (5) Is the binding of E7 to Rb sufficient for immortalization or is the binding of other cellular proteins necessary? (6) Is the primary effect of E7 binding to Rb to free transcriptional regulatory factors?
| McIntyre, M C; Ruesch, M N; Laimins, L A (1996) Human papillomavirus E7 oncoproteins bind a single form of cyclin E in a complex with cdk2 and p107. Virology 215:73-82 |
| Lechner, M S; Laimins, L A (1994) Inhibition of p53 DNA binding by human papillomavirus E6 proteins. J Virol 68:4262-73 |
